Tetrahydro-Benzo[ c ]azepines David Dumoulin, Stphane Lebrun, Axel - PDF document

[a007] UMR CNRS U niversité des 8009 COM S ciences et T echnologies de L ille S ynthèse O rganique, R éactivité, F onctionnalisation Asymmetric Synthesis of 1- ,3- or 4-Alkyl- or Aryl- Tetrahydro-Benzo[ c ]azepines David Dumoulin, Stéphane Lebrun, Axel Couture,* Éric Deniau, Pierre Grandclaudon UMR CNRS 8009 "Chimie Organique et Macromoléculaire", Université des Sciences et Technologies de Lille 1, Laboratoire de Chimie Organique Physique, Bâtiment C3(2), F-59655 Villeneuve d'Ascq Cedex, France *Axel.Couture@univ-lille1.fr Abstract: Flexible routes for the stereoselective synthesis of a variety of structurally diverse 1-, 3- or 4-alkyl and aryl-tetrahydrobenzo[c]azepines have been developed. The key steps are the highly diastereoselective 1,2-addition process or metallation/alkylation sequence applied to stereopure hydrazones. Subsequent cyclomethylenation or ring- closing metathesis reaction to secure the formation of the seven-membered azaheterocycle ring system complete the assembly of the targeted titled compounds. Introduction Benzazepines play an important role in heterocyclic chemistry because this ring system lies at the heart of a great variety of poly and diversely functionalized models endowed with profound chemotherapeutic properties [1]. Thus compounds containing the benzazepine skeleton, mainly at the tetrahydro level, display important physiological properties and are known to exhibit strong neuroleptic and neurotropic activities [2]. Some representatives have been found to display anti-HIV activity [3], to promote healing of skin wounds [4] and to treat cardiovascular diseases, especially glaucoma and hypertension [5]. Compounds of this class are also used as antiarrythmic [6] and CNS agents [7], as inhibitors of PNMT [8] and are recommended for the treatment of stomach disorders [9]. Finally the benzazepine nucleus represents the main structural unit of many naturally occurring molecules, namely those extracted from Cephalotaxus Harringtonia , Papaveraceae and Amaryllidaceae alkaloids which could be used in the treatment of Alzheimer disease [10], the most common cause of elderly dementia.

Due to the diverse biological activities of many of their derivatives the chemistry of 2- benzazepines has been the focus of new synthetic methodologies during the past decades [1] but only few of them allowed the control of stereogenic centers on the seven- membered azaheterocyclic unit. Therefore the development of synthetic methodologies which may find generality for constructing a variety of tetrahydrobenzo[ c ]azepines with alkyl or aryl appendages at C1, C3 and C4 in a stereo and enantioselective manner constitutes an area of current interest. Herein we report straightforward, feasible and highly stereoselective routes to these alkylated and arylated tetrahydrobenzo[ c ]azepines 1 - 3 (Fig. 1). R 1 R 1 R 1 R 5 R 2 R 2 R 2 (R or S ) R 6 R 3 R 3 R 3 N N N H H H R 4 R 4 R 4 R 7 1 2 3 Figure 1. The Synthetic Strategy The new synthetic route to 4- or 3-alkyl(aryl)tetrahydrobenzo[ c ]azepines 1 , 2 hinges upon the combination of the highly diastereoselective metallation/alkylation reaction or nucleophilic 1,2-addition reaction to chiral aliphatic hydrazones with a cyclomethylenation reaction (Scheme 1). R 1 R 1 R 1 R 5 R 2 R 2 R 2 (R or S ) R 6 R 3 R 3 N R 3 N N H H SMP R 4 R 4 R 4 metallation/alkylation 1,2-addition process 1 reduction 2 methylenation methylenation Scheme 1. For the assembly of the 1-alkyltetrahydrobenzo[ c ]azepines 3 the key step is a highly diastereoselective 1,2-addition process applied to a stereopure aromatic hydrazone combined with a ring-closing metathesis (Scheme 2). R 1 R 1 R 1 O R 2 R 2 R 2 O O R 3 R 3 R 3 N NH N SMP SMP R 4 R 4 R 4 R 7 R 7 3 Scheme 2.

Asymmetric Synthesis of 4-Aryl or Alkyl-Tetrahydro- Benzo[ c ]azepines ( 1 ). OMe SMP = N OMe H 2 N N 1. LDA , THF R 1 R 1 0 ° C to -90 ° C CH 2 Cl 2 , MgSO 4 R 2 R 2 2. R 5 X r.t. , 12 h R 3 R 3 O N SMP R 4 R 4 R 1 R 5 R 2 ( R or S ) 1. LDA , THF R 3 0 ° C to -90 ° C N SMP 2. R 4 OMe R 1 H 2 N R 2 N Br R 3 R 5 R 5 CH 2 Cl 2 , MgSO 4 R 4 LiAlH 4 r.t. , 12 h (2 equiv) , THF , O N SMP r.t. , 12 h MOMCl (1equiv) R 1 R 1 R 5 R 5 ACOH , reflux ,1h , R 2 R 2 (R or S ) then r.t. , 1 h ( R or S ) R 3 R 3 N HN SMP SMP R 4 R 4 1. BH 3 .THF (10 equiv) C , then ∆ , 48 h THF , 0 ° 2. 10% aq NaOH , ∆ , 1 h R 1 R 5 R 2 (R or S ) 1a-g R 3 N H R 4 Scheme 3.

Table 1. Tetrahydrobenzazepines 1a-g Prepared. R 1 R 2 R 3 R 4 R 5 Benzazepines 1a-g (Yield) ( R )- 1a (58%) H MeO MeO MeO Me ( R )- 1b (48%) H MeO MeO MeO Bn ( R )- 1c (49%) H MeO MeO MeO CH 2 OMe ( R )- 1d (53%) H MeO MeO H Me ( S )- 1d (55%) H MeO MeO H Me ( R )- 1e (48%) H MeO MeO MeO Ph ( S )- 1f (52%) MeO MeO H H C 5 H 11 ( R )- 1g (51%) H OCH 2 O H (CH 2 ) 2 OBn Asymmetric Synthesis of 3-Alkyl-Tetrahydro-Benzo[ c ]azepines ( 2 ). 1. R 6 Li (3 equiv) , THF , MOMCl (1equiv) , R 1 R 1 -78 ° C to r.t. ACOH , reflux ,1 h , R 2 2. H 3 O + R 2 then r.t. , 1 h R 6 R 3 R 3 N HN SMP SMP R 4 R 4 1. BH 3 .THF (10 equiv) , THF , 0 ° C , R 1 R 1 then ∆ , 48 h R 2 R 2 2. 10% aq NaOH , ∆ , 1 h R 6 R 6 R 3 R 3 N N SMP H R 4 R 4 2a-c Scheme 4. Table 2. Tetrahydrobenzazepines 2a-c Prepared. R 1 R 2 R 3 R 4 R 6 R 6 Li Benzazepines 2a-c (Yield) ( R )- 2a (58%) H MeO MeO MeO Me CH 3 Li ( R )- 2b (53%) H MeO MeO H Me CH 3 Li ( R )- 2c (56%) H MeO MeO H C 6 H 13 C 6 H 13 Li

Asymmetric Synthesis of 1-Alkyl-Tetrahydro-Benzo[ c ]azepines ( 3 ). 1. Synthesis of the Styrenic Enehydrazides (4a-g) 1. n BuLi , THF, -78 ° C OH HO R 1 R 1 O O 2. DMF APTS , toluene , R 2 R 2 -78 ° C to r.t., 3 h ∆ , 5 h H O R 3 R 3 (74-91%) Br Br R 4 R 4 OMe H 2 N N R 7 Li , 3 equiv R 1 R 1 O O THF, 3 h , CH 2 Cl 2 , MgSO 4 , R 2 R 2 r.t., 12 h -78 ° C to r.t. O O H R 3 R 3 N SMP R 4 R 4 O Cl O (5 equiv) FeCl 3 , 6H 2 O R 1 R 1 O O CH 2 Cl 2 , Et 3 N , toluene R 2 R 2 ∆ , 12 h r.t. , 6 h O O H R 3 N R 3 O N SMP R 4 R 4 R 7 R 7 SMP + Br − R 1 R 1 CH 3 P(C 6 H 5 ) 3 O R 2 R 2 n BuLi , THF, ∆ , 12 h H O R 3 OMe N R 3 N N R 4 R 4 O R 7 R 7 SMP 4a-g (de > 95%) Scheme 5.

2. Synthesis of 1-Alkyl-Tetrahydro-Benzo[c]azepines via RCM R 1 R 2 N N Mes Mes Grubbs O Cl catalyst, Ru R 3 N 2 nd generation Ph OMe Cl PCy 3 R 4 N R 7 3 mol % , toluene, ∆ , 6 h 4a-g or 5 mol % , toluene, ∆ , 12 h or 8 mol % , toluene, ∆ , 12 h R 1 R 1 R 2 R 2 and/or O O R 3 NH R 3 N R 4 R 7 SMP R 4 R 7 5b-d,f,g 6a-e H 2 , Pd/C H 2 , Pd/C path b path a EtOH , EtOH , r.t. , 12 h r.t. , 12 h R 1 R 1 MMPP , MeOH R 2 R 2 r.t. , 48 h O O R 3 R 3 N NH SMP R 4 R 4 R 7 R 7 7b-d,f,g 8a-g for 8a,b (68-81%) LiAlH 4 , THF, ∆ , 3 h for 7b R 1 BH 3 .THF (15 equiv) R 2 C , then ∆ THF, 0 ° 73% R 3 NH R 4 R 7 3a,b Scheme 6.

Noteworthy the expected diastereopure dihydrobenzazepinones ( 5b-d,f,g ) were obtained along with the NH free ( R )-dihydrobenzazepinones ( 6a-e ) released from the chiral appendage, probably due to the N-N bond cleavage catalyzed by the efficient ruthenium catalyst (Scheme 6, Table 3). However the formation of compounds 5 and 6 was not detrimental to the outcome of the synthetic process liable to give access to the targeted titled compounds 3 (Scheme 6, paths a & b). Table 3. Compounds 3-8 Prepared R 1 R 2 R 3 R 4 R 7 4a-g 5 and/or 6 8 8 3 from 6 from 5 via 7 (Yield %) 4a (56) 50 [a] 8a (90) 3a (68) H OMe OMe OMe CH 3 (CH 2 ) 3 - - 4b (69) 8b (74) 3b (81) H H H H Me 72 - - 4b 41 [a] 8b (90) 3b (73) 38 - 4c (47) 48 [a] 8c (92) 8c (56) H H H H CH 3 (CH 2 ) 3 43 - 4d (41) 42 [a] 8d (95) 8d (52) H H H H CH 3 (CH 2 ) 5 11 - 4e (57) 48 [a] 8e (90) H OCH 2 O H CH 3 (CH 2 ) 3 - - - 4f (66) 8f (64) H OCH 2 O H Me 41 - - - 4g (48) 8g (50) H OMe OMe H Me 54 - - - [a] After extended reaction time (12 h). Conclusion We have developed flexible and efficient routes for the stereoselective synthesis of an array of constitutionally diverse 1-alkyl, 3- or 4-aryl or alkyl-tetrahydrobenzo[ c ]azepines. The key steps are the highly diastereoselective metallation/alkylation and nucleophilic 1,2- addition applied to SAMP-hydrazones combined with RCM or cyclomethylenation reactions. References (a) Kasparek, S. Adv. Heterocycl. Chem . 1974 , 17 , 45. (b) Kametani, T.; Fukumoto, K. [1] Heterocycles 1975 , 3 , 931. (c) Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org. Chem . 2001 , 5 , 519. (a) Chumpradit, S.; Kung, H. F.; Billings, J.; Kung, M. P.; Pan, S. J. Med. Chem . 1989 , 32 , [2] 1431. (b) Berger, J. G.; Chang, W. K.; Gold, E. H.; Elliott, A. J. U.S. Patent 4 996 202, 1991; Chem. Abstr. 1991 , 115 , 71420. (c) Trybulski, E. J. Eur. Patent Appl. 14 454, 1980; Chem. Abstr. 1984 , 94 , 30587. (d) Berger, J. G.; Chang, W. K.; Clader, J. W.; Hou, D.; Chipkin, R. E.; McPhail, A. T. J. Med. Chem . 1989 , 32 , 1913. (e) Ohnmacht Jr., C. J.; McLaren, F. M. J. Heterocycl. Chem. 1991 , 28 , 1219. (f) Berger, J. G.; Chang, W. K.; Clader, J. W. PCT Int; Appl. WO Patent 9 205 157, 1992; Chem. Abstr. 1992 , 117 , 171248. (g) Berger, J. G.; Chang, W. K.; Gold, E. H.; Clader, J. W. Eur. Patent 299 101, 1989; Chem. Abstr. 1989 , 114 , 173116. (h) Schering Corp. IS patent 83 211, 1991; Chem. Abstr. 1992 , 117 , 171247. (i) Efange, S. M. N.; Mash, D. C.; Khare, A. B.; Ouyang, Q. J. Med. Chem . 1998 , 41 , 4486. (j) Itil, T. M.; Stock, M. J.; Duffy, A. D.; Esquenazi, A.; Saleuty B.; Han T. H. Curr. Ther. Res . 1972 , 14 , 136. (k) Albert, J. M.; Elie, R.; Cooper, S. F.; Clermont, A.; Langlois, Y. Curr. Ther.